Objective: We investigated mechanisms of colorectal cancer (CRC)
chemoresistance to first-line chemotherapy (capecitabine plus oxaliplatin (XELOX)) and
identified two putative chemoresistant microRNAs, miR-1914* and -1915, that are downregulated
in plasma samples from patients with chemoresistant CRC.
Methods: A number of plasma samples from CRC patients were analyzed for the levels of miR-1914* and -
1915. Effects of stable and transient expression of 2 microRNAs in human chemoresistant CRC cell lines were
analyzed. Tumor formation and chemoresistance in HCT116/5-Fu/OXA that did or did not express 2
microRNAs were analyzed in mice. Nuclear factor I/X (NFIX) was predicted to target the gene of 2 miRNAs
and verified in vivo and in vitro.
Results: Plasma levels of miR-1914* and -1915 in chemoresistant CRC patients were different than levels in
responders, and associated with clinical response. Overexpression of miR-1914* and -1915 in chemoresistant
CRC cells reduced resistance to 5-FU and Oxaliplatin in vitro. The microRNAs suppressed chemoresistance in
CRC tumors in mice by affecting cell growth, invasion, apoptosis and tumor suppressor function. miR-1914*
and -1915 interacted with the 3’-untranslated region of NFIX and reduced NFIX its level in chemoresistant CRC
cells. Overexpression of NFIX did not inhibit chemoresistant CRC cell motility and chemoresistant proteins
when miR-1914* and -1915 were transfected.
Conclusion: Plasma miR-1914* and -1915 interact with NFIX RNA and reduce its level in chemoresistant CRC
cells to first-line chemotherapy. Up-regulation of miR-1914* and -1915 decreased the chemoresistance abilities
of chemoresistant CRC cells. The plasma miR-1914* and -1915 may play a role in colorectal cancer therapy